Swelling Thermodynamics and Kinetics of Crosslinked Polystyrene Resin in Solid‐Phase Synthesis

ABSTRACT Cross‐linked polymer resins are widely used as solid supports in solid‐phase synthesis (SPS), where access to internal reactive sites depends on swelling of the gel‐like polymer network. Despite its central role, swelling lacks well‐defined physical metrics, limiting the rational design of SPS processes and reactor systems. Here, we investigate the swelling behavior of spherical polystyrene–divinylbenzene (PS–DVB, 1% cross‐linked) resins in dichloromethane (DCM) and dimethylformamide (DMF) from both thermodynamic and kinetic perspectives. Combining the Flory–Rehner framework with Hansen solubility parameters, we show that attached glycans increase polymer–solvent affinity toward DCM, whereas peptides reduce it. The equilibrium swelling degree exhibits only a weak temperature dependence, while swelling kinetics in packed‐bed geometries are strongly temperature dependent: relaxation times in DCM increase from 18 s at 20°C to 35 s at −30°C. These results establish quantitative time scales for resin swelling under SPS conditions and provide a mechanistic basis for using resin‐volume changes as a real‐time indicator of reaction progress.